Skin Aging and Cellular Senescence: History
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Subjects: Cell Biology
Skin aging is a result of two cumulative and overlaying mechanisms denominated as intrinsic and extrinsic aging. The process of intrinsic or chronological aging affects all tissues and organs of the body, is due to the passage of time, and is influenced by genetic background. However, the skin is continuously exposed to environmental and lifestyle factors such as sunlight, pollution, cigarette smoke, and dietary habits. These factors, collectively denominated the skin exposome, are the major causes of the process of extrinsic skin aging. In addition, cellular senescence and the accumulation of senescent cells in the skin is considered as a hallmark of aging. Senescent cells contribute to the decline of tissue function and lead to age-related changes and pathologies.
  • Cellular Senescence
  • Skin Aging
  • Skin Inflammation

1. Cellular Senescence

Cellular senescence, which is considered one hallmark of aging, is defined by a state of proliferative arrest and is known to be involved in tumor suppression and progression, tissue remodeling, and embryonic development [14]. The accumulation and persistence of senescent cells is an important characteristic of aging of some tissues, including the skin [15]. Senescent cells contribute to the decline of tissue function and lead to age-related changes and pathologies [16]. This well-known interconnection between cellular senescence, skin aging, and skin diseases is often related to molecular processes such as inflammation.
Senescent cells are characterized by several characteristics such as a distinct morphology [17], DNA damage [18], cell cycle arrest [19], mitochondrial dysfunction [20], protein quality impairment [21], inflammation [22], and reactive oxygen species (ROS) generation [23]. Additionally, senescent cells are not able to proliferate as they reside in a cell cycle arrest, which is mostly caused by an accumulation of DNA damage [24,25]. If unrepaired, these damages lead to detrimental effects such as cellular dysfunction and cancer. Other features of senescent cells are the appearance of senescence-associated heterochromatin foci (SAHF) and decreased Lamin B1 expression [14].
Importantly, some types of senescent cells can also be recognized by other characteristics, such as increased senescence-associated β-galactosidase (SA-β-Gal) activity and the secretion of a set of pro-inflammatory factors, the so-called senescence-associated secretory phenotype (SASP) [26]. In general, SASP components can have beneficial effects such as recruitment of immune cells, promotion of anti-tumor response, and improved wound healing [26]. On the other hand, SASP components can contribute to the functional disruption of tissue structure in an autocrine and paracrine manner leading to the senescence of the neighboring cells via paracrine communication, immunosuppression, and inflammation [26,27]. The composition of the SASP is determined by the type of senescence and cell type but the most common cytokines upregulated in cutaneous skin cells during aging are interleukin (IL)-1 and IL-6, as well as the matrix metalloproteases (MMP)-1 and MMP-3 [26,28].
Another hallmark of senescent cells is the imbalance between their production of ROS and their ability to detoxify the reactive intermediates [29,30]. Elevated ROS levels cause damage to cellular molecules such as proteins, lipids, and nucleic acids as well as to organelles such as mitochondria and proteasomes [31]. Antioxidant enzymes such as glutathione and superoxide dismutase are able to stabilize or deactivate free radicals before they attack cellular components, avoiding the so-called oxidative stress. During senescence these defense mechanisms are decreased whereas the ROS is continuously produced and the cells become more prone to oxidative damage [32]. ROS can induce the mitogen-activated protein kinase (MAPK)-p38 pathway which leads to further activation of p53-p21 and cell cycle arrest and thus initiating or accelerating the senescence process [14]. Besides this, excessive ROS induce inflammation-related pathways such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, which regulates different intracellular responses such as apoptosis, cell proliferation, angiogenesis, metastasis, and tumor promotion [7].
Mitochondrial damage, another feature of senescent cells, results from accumulation of mitochondrial DNA mutations, dysfunction and structural alterations of important mitochondrial proteins and membranes, imbalance of fission and fusion, and impaired mitophagy which, in turn, results in increased ROS production and decreased energy generation by oxidative phosphorylation [20,33]. Mitochondria are the main intracellular sources of ROS and excessive ROS production can lead to fragmentation of mitochondria by modulation of mitochondrial fission and fusion proteins [34] and impairment of mitostasis is considered to be one of the causes of cellular senescence [20].
During senescence, the intracellular mechanisms of protein quality control, autophagy and the proteasome, are impaired. Autophagy is responsible for the elimination of damaged or excessive proteins and organelles via the lysosomes, whereas the proteasome especially degrades oxidized proteins [35]. Generally, the activity and function of both mechanisms are reduced with age and senescence [21,24]. For instance, decreased expression of genes that transcribe proteasome subunits as well as modifications of these subunits are considered as major drivers of the age-related impairment of proteasome activity [36]. Proteasome activity has been reported to be decreased in photoaging models of keratinocytes [37], melanocytes [17], and fibroblasts [31]. Furthermore, in senescent melanocytes and fibroblasts the impairment of the proteasome was compensated by an increase of autophagy as an alternative mechanism of protein quality control [17,31]. Impaired autophagy has been related to reduction in lysosomal proteolytic function, decreased rates of autophagolysosomal fusion, and impaired delivery of autophagy substrates to lysosomes, which leads to the intracellular accumulation of undigested material, exacerbates cellular impairment, and contributes to the development of senescence and in tissue to age-related diseases [21,38,39].

2. Cellular Senescence and Skin Aging

2.1. Main Characteristics of Skin Aging

The skin is constituted of many different cell types, including, among others, fibroblasts, keratinocytes, and melanocytes. Skin aging is a multifactorial process and most if not all skin cell types, when functionally impaired, can potentially contribute to the deterioration of the tissue [15]. Additionally, the skin is a useful system for the investigation of aging since this tissue undergoes morphological, biochemical, and functional modifications during the process of aging.
Skin aging is characterized by different features, one of which is the accumulation of damaged and dysfunctional macromolecules in the skin cells due to decreased function of autophagy and proteasome activity. Autophagy plays a role in extrinsic and intrinsic skin aging and regulates pigmentation, homeostasis, and the functions of fibroblasts, keratinocytes, and melanocytes [21,39]. In fibroblasts, it was shown that impaired autophagic flux induced by inhibition of lysosomal proteases lead to the decreased expression of hyaluron, elastin, and type 1 procollagen, and to the increased breakdown of collagen fibers which result in the impairment of dermal integrity and increased skin fragility [40]. In melanocytes, several groups showed that modulation of autophagy can induce cellular senescence and impairment of antioxidant defense mechanisms leading to changes in skin pigmentation [41,42]. Additionally, autophagy and oxidative stress are determinant factors in the fate of keratinocytes and control their progression to senescence, programmed cell death, or tumor formation [21,39].
During aging, skin cells also accumulate damaged mitochondria and mitochondrial DNA deletions leading to structural and functional alterations in the extracellular matrix (ECM) and the induction of inflammation which, in turn, accelerate the formation of skin wrinkles [18].

2.2. Inflammation and Skin Aging

Inflammation is one of the main pathways involved in the process of skin aging. Furthermore, chronic inflammation can lead to skin disorders such as AD and psoriasis [43]. AD is a skin inflammatory disease with symptoms such as pruritus, itching, pain, and sleep disturbance [44,45]. Several different pathways are involved in the activation of inflammation. Here, we will focus on three main activators of inflammation recognized to be involved in skin aging.
The first pathway involves the aryl hydrocarbon receptor (AhR), a transcription factor highly expressed in all cutaneous cell types which has been reported to play a key role in the maintenance of skin barrier, regulation of skin pigmentation, and skin immunity. In humans, the highly conserved AhR has a complex role. Different ligands such as polyaromatic hydrocarbons (PAH) can bind and activate AhR. This leads to AhR translocation to the nucleus where it regulates the expression of genes such as cytochrome P450 1A (CYP1A) which can, in turn, further induce oxidative damage by generating ROS [46]. Alterations in AhR signaling lead to dysregulated skin barrier function and can generate symptoms such as dryness, itchiness, and flakiness which are similar symptoms to AD [46,47,48]. In mice, depletion of AhR leads to transepidermal water loss, decreased expression of important barrier function proteins such as filaggrin and involucrin, and changes of the skin microbiome [49]. In chronic skin inflammation diseases such as psoriasis, activation of AhR can determine the severity of the symptoms [50]. In addition, the activation of AhR is crucial for melanocyte survival and melanogenesis which are events that can be linked to the appearance of senile lentigines [51].
The second important inflammatory pathway participating in skin aging is controlled by NF-κB, a transcription factor which resides in the cytoplasm and, if activated, translocates to the nucleus. Activation of the NF-κB signaling pathway is driven by the response to diverse stimuli, including ligands of various cytokine receptors, pattern-recognition receptors (PRRs), T-cell receptor (TCR) and B-cell receptors, as well as to a subset of TNF receptor (TNFR) superfamily members such as LTβR, BAFFR, CD40, and RANK [52]. Once translocated to the nucleus, NF-κB promotes the production and release of tumor necrosis factor-α (TNF-α), MMPs, and other SASP components such as IL-1α, and cyclooxygenases (COX)-1 and -2. These factors can reinforce the inflammation process and accelerate the skin aging process [53,54]. Importantly, the dysregulation of NF-κB plays an important role in the pathogenesis of chronic inflammatory diseases of the skin as well as in wound healing [55].
The third important inflammatory signaling pathway involved in skin aging is coordinated by nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE). Nrf2 is an important transcription factor in the inflammation signaling cascade as well as in oxidative stress responses and is responsible for the expression of ARE genes such as heme oxygenase-1. Nrf2 can also negatively regulate NF-κB activation either by directly decreasing intracellular ROS levels or by inhibiting the translocation of NF-κB to the nucleus [56,57]. Recently, it was demonstrated that senescent melanocytes increased the expression of Nrf2 which was accompanied by decreased melanogenesis [58]. Nrf2 depletion in skin cells leads to the reduction of cell survival as well as induction of oxidative stress while mutations in the Nrf2 gene, in turn, lead to the development of squamous cell carcinoma suggesting that pathways activated by Nrf2 are important for the maintenance of skin homeostasis [59].

2.3. Senescence of Skin Cells and Skin Aging

The accumulation of senescent cells in the epidermis and dermis is considered as a hallmark of aging. The occurrence of senescent cells can be accelerated by exposition of the skin to different sources of environmental and lifestyle factors [15,60]. Senescent fibroblasts display different senescence associated characteristics such as cell cycle arrest, decreased autophagy activity, increased SA-β-Gal activity, mitochondrial dysfunction, DNA damage, increased ROS generation, and increased expression of SASP factors [31,61]. The appearance and persistence of senescent fibroblasts in the dermis leads to the accumulation of elastotic material, which results from the incomplete degradation of elastic fibers, as well as to the decreased expression of extracellular matrix components simultaneously to the increased degradation of ECM. These events are manifested in dullness and reduced elasticity of the skin [1,62]. Keratinocytes are constantly renewed and more prone to apoptosis than senescence when confronted by stressors. Nevertheless, keratinocytes contribute greatly to the aging process by losing the ability to terminally differentiate or proliferate and responding differently to external stimuli [15]. Senescent keratinocytes express increased p15, IL-1α, and high mobility group A2 [27]. Other hallmarks of senescence such as SA-β-Gal, expression of p21, p53, and p16 are displayed in keratinocytes upon UVB exposure [16]. Senescence of melanocytes has been insufficiently explored but a recent study has reported that senescent melanocytes accumulate in human skin where they contribute to aging of this tissue by impairing proliferation of the neighboring keratinocytes [63]. Melanocytes’ senescence can occur either by exhaustion of their replicative capacity, in a process called replicative senescence, or by stress-induced premature senescence in which senescence is triggered by chronic exposition of these cells to sublethal doses of a stressor agent such as UV or ROS-inducing agents [17,25]. Accumulated senescent melanocytes in skin is correlating with visible signs of skin aging such as facial wrinkling and deposition of elastin in the dermis [60]. Although melanocytes become age-dependently less active, darker pigmented spots, also described as age spots, solar lentigines, or lentigo senilis, are a common characteristic of aged skin, presumably occurring due to irregularities in melanocyte distribution, enhanced melanogenic signaling and decreased melanosome removal [15,64]. Besides the impairment of melanocytes, the dysregulated secretion of molecules produced by aged keratinocytes and fibroblasts cause the occurrence of senile lentigines [15,51]. For example, UV-induced senescent fibroblasts contribute to the formation of age spots by decreasing the expression and secretion of stromal cell-derived factor 1 [65], emphasizing the complexity of underlying factors driving skin aging and the development of senile lentigines.

2.4. Microbioma and Skin Aging

Another important but as yet less investigated change that occurs in the skin during aging is the alteration of the skin microbiome. The human skin microbiome consists of bacteria, fungi, viruses, archaea, and other microorganisms which are essential for body homeostasis and when dysregulated can contribute to diseases [45,66]. The skin of young individuals is rich in bacteria of the Firmicutes phylum but with age, these are replaced by Bacteroides and Proteobacteria. This imbalance of commensal skin microbes which produce immune factors affects the skin’s immune system, explaining the increased risk of pathogenic invasions and age-related skin disorders [22,67].

2.5. Skin Aging in Different Ethnicities and Phototypes

In humans, melanin determines skin and hair color and is responsible for photoprotection against UV radiation. Melanin molecules surround the nuclei of the keratinocytes and melanocytes to protect their genetic material, by absorbing sunlight through the polymeric melanin molecule [68,69]. The differences in skin color are mainly determined by the type and amount of melanin produced by melanocytes which is a major factor of skin aging. Melanocytes can produce two different types of melanin. Eumelanin, a brown-black pigment, and pheomelanin, a yellow-red pigment [70]. Melanocytes transfer melanin to the neighboring keratinocytes, and melanin is degraded during keratinocytes differentiation. The ratio of melanin degradation determines the skin pigmentation and, consequently, the skin phototypes. For instance, in fair skin phototypes melanosomes are almost completely degraded, whereas in dark skins they barely undergo degradation and accumulate in the upper layers of the epidermis [1]. During the process of skin aging, the density and activity of melanocytes is continuously decreased, while the percentage of cells with impaired melanin synthesis is increased [15], leading to the appearance of skin pigmentation issues.
Given the differences in skin pigmentation and degradation of melanin, skin aging manifests differently among different skin phototypes and ethnicities. For instance in Asians and African Americans pigmentation changes are considered early manifestations of skin aging, whereas aging of Caucasian skin is characterized in its early stages by the appearance of wrinkles [71,72,73].
In general, highly pigmented skin structurally consists of a thicker dermis and stratum corneum which contribute to increased resistance and elasticity in comparison to light pigmented skin [71,74]. Recent studies demonstrated that highly pigmented skin exposed to UV displays a deposition of collagen and elastic network, a decrease in epidermal thickness [75], lightening of skin [76], as well as production of MMPs [77]. Upon skin aging, light pigmented skin exhibits thinner and less compact stratum corneum, deposition of elastic fibers, impairment of barrier function, reduction of sebum, production of MMPs, and loss of collagen [71,74]. These findings indicate that skin aging mechanisms seem to be similar between ethnicities. However, further investigations are necessary to understand the underlying molecular processes of different ethnic skin types.
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